EP0849267B1 - Furoindolizine - Google Patents

Furoindolizine Download PDF

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Publication number
EP0849267B1
EP0849267B1 EP97122290A EP97122290A EP0849267B1 EP 0849267 B1 EP0849267 B1 EP 0849267B1 EP 97122290 A EP97122290 A EP 97122290A EP 97122290 A EP97122290 A EP 97122290A EP 0849267 B1 EP0849267 B1 EP 0849267B1
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EP
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Prior art keywords
ucs1025
strain
compounds
compound
salts
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English (en)
French (fr)
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EP0849267A1 (de
Inventor
Tamio Mizukami
Harumi Ogawa
Ryuichiro Nakai
Akira Asai
Yoshinori Yamashita
Katsuhiko Ando
Tsutomu Agatsuma
Shiro Akinaga
Kozo Ouchi
Hideki Kawasaki
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KH Neochem Co Ltd
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Kyowa Hakko Kogyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring

Definitions

  • the present invention relates to UCS1025 compounds, tautomers chemically equivalent thereto, and pharmacologically acceptable salts thereof. These materials have antibacterial and antitumor activities and are useful as antibacterial agents and antitumor agents.
  • An object of the present invention is to provide compounds which have excellent antibacterial and antitumor activities.
  • UCS1025 compounds represented by the following formula (I): (wherein R represents hydrogen or hydroxyl group) , tautomers chemically equivalent thereto, or pharmacologically acceptable salts thereof, which compounds, tautomers and salts have antibacterial and antitumor activities.
  • the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient, an effective amount of one of the compounds, tautomers or salts (referred to hereinafter collectively as "UCS1025 compounds”) defined above.
  • UCS1025A exists as an equilibrium mixture of three compounds such as a keto type (I)a, an enol type (II)a, and a carboxyl type (III)a, and their composition ratio widely varies depending on the conditions, such as solvent, temperature and the like. Such tautomers, stereoisomers thereof and mixtures of these compounds at all ratios are included in the present invention.
  • the physicochemical properties of UCS1025 compounds are shown below.
  • the present compounds exist as a mixture of tautomers chemically equivalent thereto. Accordingly, the mixture ratios of these compounds widely vary depending on the conditions of sample obtaining and measuring and are not definite.
  • the following data relate to the samples which were obtained by the methods shown in the following examples. In 1 H- and 13 C-nuclear magnetic resonance spectrum, each signal of the tautomers are possible to measure and distinguish, so the data of these tautomers are shown separately.
  • the physicochemical properties were measured by the following apparatus:
  • UCS1025 compounds can be obtained by culturing in a medium a microorganism belonging to the genus Acremonium or Humicola and having the ability to produce UCS1025 compounds, thereby allowing UCS1025 compounds to accumulate in the culture, and recovering them from the culture.
  • any strain can be used, insofar as it belongs to the genus Acremonium or Humicola and can produce UCS1025 compounds.
  • any mutant of such strains which are obtained by various artificial mutation methods, such as ultraviolet ray irradiation, X-ray irradiation, mutagen treatment or the like, or by spontaneous mutation can be used in the present invention, insofar as they have the ability to produce UCS1025 compounds.
  • preferred strains include Acremonium sp. KPC 7629-19 strain and Humicola sp. KPC 7781-6 strain.
  • the inventors of the present invention have found that a fungal strain KPC 7629-19 belonging to the genus Acremonium and a fungal strain KPC 7781-6 belonging to the genus Humicola , newly isolated from soil, can produce UCS1025 compounds having antibacterial and antitumor activities.
  • a typical strain (KPC 7629-19) capable of producing the compound of the present invention has been isolated from a soil sample, and the mycological properties thereof are as follows:
  • the diameter of a colony reaches 16 to 21 mm on the 7th day of culturing and 28 to 31 mm on the 14th day of culturing.
  • Central part of the colony surface shows a grayish brown color and its peripheral is beige or grayish white.
  • Central part of the reverse side of the colony shows a reddish brown color and its peripheral is beige or grayish liver brown. Also, it produces an orange pigment in the media.
  • the diameter of a colony reaches about 15 mm on the 7th day of culturing and about 25 mm on the 14th day of culturing.
  • Central part of the colony surface becomes a radial wrinkled shape and shows a cream to brown color and its peripheral is gray.
  • Central part of the reverse side of the colony shows a light brown to liver brown color and its peripheral is grayish white.
  • the growth temperature range for this strain is 11 to 31°C, and the optimum growth temperature is around 23°C.
  • the pH range which allows its growth is 3 to 10, and the optimum growth pH is around 6.
  • the conidium is subspherical to elliptical, colorless and smooth and is 2.5 to 4.5 ⁇ m long and 1.7 to 2.5 ⁇ m wide. Also, it forms a spherical to subspherical chlamydospore having 2.5 to 5.5 ⁇ m diameter.
  • KPC 7781-6 Another typical strain (KPC 7781-6) capable of producing the compounds of the present invention has been also isolated from a soil sample, and it has the following mycological properties.
  • diameter of colony reaches 40 to 50 mm on the 7th day of culturing and 63 to 75 mm on the 14th day of culturing.
  • the surface of the colony is slightly greenish and grayish white to gray and its peripheral is blackish brown.
  • the reverse side of the colony shows a blackish brown color and its peripheral sometimes shows a creamy color.
  • the diameter of the colony reaches 39 to 46 mm on the 7th day of culturing and 65 to 70 mm on the 14th day of culturing.
  • Central part of the colony surface is white and the peripheral is blackish gray.
  • the reverse side of the colony shows a blackish brown color and the central part sometimes shows a beige color.
  • the growth temperature range for this strain is 11 to 33°C, and the optimum growth temperature is at around 27°C. It can grow at pH 3 to 12, and the optimum growth pH is around 6.
  • the UCS1025 compound-producing strains of the present invention usually used fungi culturing method can be employed.
  • the medium either a synthetic medium or a natural medium can be used, insofar as it properly, for example, contains carbon sources, nitrogen sources, inorganic compounds and the like which can be assimilated by the strains employed.
  • carbon sources examples include glucose, starch, dextrin, mannose, fructose, sucrose, lactose, xylose, arabinose, mannitol, molasses and the like, which may be used alone or in combination thereof.
  • hydrocarbons, alcohols, organic acids and the like can also be used.
  • nitrogen sources examples include ammonium chloride, ammonium nitrate, ammonium sulfate, sodium nitrate, urea, peptone, meat extract, yeast extract, dry yeast, corn steep liquor, soybean powder, casamino acid and the like, which may be used alone or as a mixture thereof.
  • sodium chloride, potassium chloride, magnesium sulfate, calcium carbonate, potassium dihydrogenphosphate, magnesium phosphate octahydrate, ferrous sulfate, calcium chloride, manganese sulfate, zinc sulfate, copper sulfate and the like inorganic salts may be added as occasion demands. Also, minor components which enhance growth of the strain or production of UCS1025 compounds may be added appropriately.
  • a liquid culture method particularly a submerged stirring culture method, is suitable.
  • Culturing is carried out at 16 to 37°C, preferably 25 to 32°C, and at pH 4 to 10, preferably 6 to 8, and liquid ammonia, ammonium carbonate aqueous solution and the like are used for adjusting the medium pH.
  • the culturing is completed generally after 1 to 9 days, but it is desirable to terminate the culturing when UCS1025 compound are formed and accumulated in the culture broth and cells and the produced amount in the culture mixture reaches the maximum.
  • Isolation and purification of the thus accumulated UCS1025 compounds from the culture can be effected by employing appropriate methods which are generally used for isolating and purifying usual microbial metabolites from the culture.
  • the culture is separated into culture filtrate and cells by filtration, and cell components are extracted from the cells with chloroform, acetone or the like solvent.
  • the extract and culture filtrate are combined and applied to a polystyrene based adsorbent such as Diaion HP-20 (manufactured by Mitsubishi Chemical Corp.) to effect adsorption of the active component which is subsequently eluted with methanol, acetone or the like solvent.
  • UCS1025 compounds are obtained by concentrating the eluate and treating it, for example, with octadecyl group-bonded type silica gel (ODS) column chromatography, high-performance liquid chromatography or silica gel column chromatography.
  • ODS octadecyl group-bonded type silica gel
  • Pharmacologically acceptable salts of UCS1025 compounds or tautomers of chemically equivalent thereto include pharmacologically acceptable metal salts, ammonium salts, organic amine addition salts and amino acid addition salts.
  • the metal salts include alkali metal salts (e.g., lithium salts, sodium salts, potassium salts) , alkaline earth metal salts (e.g., magnesium salts, calcium salts), aluminum salts, zinc salts and the like.
  • Examples of the ammonium salts include salts of ammonium, tetramethylammonium and the like.
  • Examples of the organic amine addition salts include addition salts of morpholine, piperidine and the like.
  • the amino acid addition salts include addition salts of glycine, phenylalanine, aspartic acid, glutamic acid, lysine and the like.
  • salts of UCS1025 compounds or tautomers chemically equivalent thereto they may be purified as such if salts of the UCS1025 compound or its chemically equivalent tautomers can be obtained, or when they are obtained in their free forms, they may be dissolved or suspended in an appropriate solvent and then made into salts by adding a base.
  • UCS1025 compounds, tautomers chemically equivalent thereto or pharmacologically acceptable salts thereof may exist in some cases in the form of addition products with water or various solvents, and these addition products are also included in the present invention.
  • UCS1025 compounds having antibacterial and antitumor activities, tautomers chemically equivalent thereto or pharmacologically acceptable salts thereof can be provided.
  • a medium (pH 6.5) composed of 100 g/L glucose, 30 g/L mashed potato base and 5 g/L yeast extract was used as the first and second seed culture media.
  • One loopful of seed strain was inoculated into 50 ml of the first seed medium contained in a 300 ml capacity conical flask and cultured at 25°C for 144 hours on a shaker.
  • a 15 ml portion of the thus obtained first seed culture (50 ml) broth was inoculated into 300 ml of the second seed medium contained in each of six 2 L capacity conical flasks and cultured with shaking at 25°C for 48 hours.
  • a 900 ml portion of the thus obtained second seed culture broth was inoculated into 18 L of a main fermentation medium contained in each of two 30 L capacity tank (36 L in total) and cultured at 25°C for 162 hours with aeration and agitation (agitation speed 300 rpm, aeration rate 18 L/min).
  • a medium (pH 6.0) composed of 20 g/L glucose, 20 g/L mashed potato base, 5 g/L peptone, 5 g/L potassium dihydrogenphosphate and 0.5 g/L magnesium phosphate octahydrate was used as the main fermentation medium.
  • a 30 L portion of the thus obtained fermentation broth was mixed with 10% of a filter aid (Radiolite #600, manufactured by Showa Chemical Industry) and filtered using a centrifugal filter.
  • the culture filtrate thus separated from the cells was applied to a column packed with 2 L of Diaion HP-20 to effect adsorption of the active components. Impurities were eluted with 6 L of 40% methanol aqueous solution and then the active components were eluted with 6 L of methanol.
  • the active fraction was concentrated to 400 ml under a reduced pressure. This was mixed with the same volume of ethyl acetate to extract the active components. When the extract was concentrated to dryness under a reduced pressure, a brown oily substance was obtained.
  • UCS1025A was produced using Humicola sp. KPC 7781-6 strain as the seed strain.
  • a medium (pH 6.5) composed of 100 g/L glucose, 30 g/L mashed potato base and 5 g/L yeast extract was used as the seed culture medium.
  • One loopful of the seed strain was inoculated into 50 ml of seed culture medium contained in a 300 ml capacity conical flask and cultured with shaking at 25°C for 72 hours.
  • a 2.5 ml portion of the thus obtained culture broth was inoculated into 50 ml of a main fermentation medium contained in each of 300 ml capacity conical flasks (40 flasks, 2 L in total) and cultured with shaking at 25°C for 216 hours.
  • a 2 L portion of the thus obtained fermentation broth was mixed with 10% of a filter aid (Radiolite #600, manufactured by Showa Chemical Industry) and filtered using a suction filter.
  • the cells thus separated from the culture filtrate were mixed with 1 L of methanol and thoroughly stirred to effect extraction and again filtered using the suction filter.
  • the thus obtained methanol extract was concentrated under a reduced pressure and then adjusted to 1 L by adding water.
  • This solution and the culture filtrate were separately applied to a column packed with Diaion HP-20, and the active component was eluted with methanol. Both of the active fractions were combined, concentrated under a reduced pressure and then adjusted to 5 L by adding water. This was applied to a column packed with Diaion HP-20ss and developed with a water-methanol mixture solution.
  • Impurities were eluted with a water/methanol (3:7, v/v) solution and then the active component was eluted with a water/methanol (2:8 - 0:1, v/v) solution.
  • the active fraction was concentrated to dryness under a reduced pressure, a brown oily substance was obtained.
  • a silica gel column (Wako Gel C-200, manufactured by Wako Pure Chemical Industries), this oily substance was developed with a chloroform-methanol-acetic acid mixture solution.
  • Impurities were eluted with a chloroform/methanol/acetic acid (1000:10:1, v/v/v) solution and then the active component was eluted with a chloroform/methanol/acetic acid (980:20:2, v/v/v) solution.
  • a chloroform/methanol/acetic acid 980:20:2, v/v/v
  • the antibacterial activity was measured by an agar dilution method on media (pH 7) -composed of 3 g/L of Bacto-tryptone (manufactured by Difco), 3 g/L of meat extract, 1 g/L of yeast extract, 1 g/L of glucose and 16 g/L of agar.
  • the antibacterial activity was shown by minimum inhibitory concentration (MIC).
  • Respective cells were dispensed into a 96 well microtiter plate (Nunc #167008) in 1 ⁇ 10 3 cells/well portions in the case of MCF-7 and T24 or in 1.5 ⁇ 10 3 cells/well portions in the case of A431 and ACHN and cultured at 37°C for 24 hours in a 5% carbon dioxide incubator. Thereafter, 30 mM of UCS1025A and 30 mM of UCS1025B were each serially diluted and added to the wells in 50 ⁇ l portions. The final concentration of each solution becomes 100 ⁇ M at the maximum at this stage. They were cultured again at 37°C for 72 hours in the 5% carbon dioxide incubator.
  • MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide, Sigma] which had been dissolved in the culture to a final concentration of 1 mg/ml was dispensed into the plate in 50 ⁇ l/well portions.
  • DMSO was dispensed in 150 ⁇ l/well portions, and the resulting plate was stirred vigorously using a plate mixer to dissolve MTT-formazan crystals completely. Thereafter, absorbance at 550 nm was measured using a microplate spectrophotometer M-SPmax250 (manufactured by Wako Pure Chemical Industries). The cell growth inhibition activity was shown by the 50% inhibitory concentration IC 50 .

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
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  • General Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Claims (9)

  1. UCS 1025-Verbindung der nachstehenden Formel (I):
    Figure 00290001
    wobei R ein Wasserstoffatom oder eine Hydroxylgruppe bedeutet, oder Tautomere davon oder pharmakologisch verträgliche Salze davon.
  2. Arzneimittel, umfassend einen pharmazeutisch verträglichen Träger und eine Verbindung gemäß Anspruch 1.
  3. Arzneimittel nach Anspruch 2, wobei R ein Wasserstoffatom bedeutet.
  4. Arzneimittel nach Anspruch 2, wobei R eine Hydroxylgruppe bedeutet.
  5. Verwendung einer Verbindung nach Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von Tumoren und bakteriellen Erkrankungen.
  6. Pilz der Gattung Humicola, als FERM BP-5674 hinterlegt.
  7. Pilz der Gattung Acremonium, als FERM BP-5673 hinterlegt.
  8. Verfahren zur Herstellung einer UCS 1025-Verbindung nach Anspruch 1, umfassend das Züchten eines Mikroorganismus, der diese Verbindung erzeugen kann, und Isolieren der Verbindung aus der Kultur.
  9. Verfahren nach Anspruch 8, wobei der Mikroorganismus wie in Anspruch 6 oder 7 definiert ist.
EP97122290A 1996-12-18 1997-12-17 Furoindolizine Expired - Lifetime EP0849267B1 (de)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP337765/96 1996-12-18
JP33776596 1996-12-18
JP33776596 1996-12-18
JP12097 1997-01-06
JP12097 1997-01-06
JP120/97 1997-01-06

Publications (2)

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EP0849267A1 EP0849267A1 (de) 1998-06-24
EP0849267B1 true EP0849267B1 (de) 2001-09-26

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US (1) US5798379A (de)
EP (1) EP0849267B1 (de)
AT (1) ATE206125T1 (de)
CA (1) CA2225209A1 (de)
DE (1) DE69706950T2 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7013305B2 (en) 2001-10-01 2006-03-14 International Business Machines Corporation Managing the state of coupling facility structures, detecting by one or more systems coupled to the coupling facility, the suspended state of the duplexed command, detecting being independent of message exchange
ATE267832T1 (de) 1998-10-23 2004-06-15 Sosei Co Ltd Substanz gm-95, verfahren zu ihrer herstellung und ihre verwendung
EP1227097A4 (de) 1999-10-21 2003-04-02 Kyowa Hakko Kogyo Kk Ucs1025-derivate
BRPI0909142B8 (pt) * 2008-03-14 2021-05-25 Astellas Pharma Inc composto cíclico e sal do mesmo, seu uso, seu processo de preparação, e composição farmacêutica
KR101566046B1 (ko) * 2008-03-14 2015-11-04 아스테라스 세이야쿠 가부시키가이샤 환형 화합물을 생산하는 미생물

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US5798379A (en) 1998-08-25
DE69706950T2 (de) 2002-04-25
EP0849267A1 (de) 1998-06-24
CA2225209A1 (en) 1998-06-18
ATE206125T1 (de) 2001-10-15
DE69706950D1 (de) 2001-10-31

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